Basically substituted alkyl esters of gamma-aroylarylbutyric acids and their salts



Patented June 9, 1953 BASICALLY SUBSTITUTED ALKYL ESTERS OF 'y-AROYLARYLBUTYRIC ACIDS AND THEIR SALTS John W. Cusic, Skokie, Ill., assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application July 3, 1950, Serial No. 172,023

17 Claims.

The present invention relates to basic esters of arylaroylaliphatic acids and, in particular, to esters of N,Ndisubstituted aminoalcohol esters of 'y-aroylbutyric acids, in which the acid is substituted in the aor B-position by a further aryl group.

The esters which constitute my invention may be represented by the structural formula wherein Ar and Ar are aryl radicals, Y is a bivalent, aliphatic hydrocarbon radical and wherein NRR' is a member of the class consisting of dialkylamino radicals and heterocyclic radicals which are attached to the Y group through a nitrogen in the heterocycle.

In the foregoing structural formula Ar and .Ar may represent such aryl groups as phenyl,

-, mand p-tolyl, o-, mand p-anisyl, fluoro-, chloro-, bromoand iodophenyl and the like. The Y group represents bivalent, saturated, aliphatic hydrocarbon radicals of from two to eight carbon atoms. These radicals are derived from straight-chain and branched-chain aliphatic hydrocarbons and include radicals such as ethylene, propylene, butylene, amylene, and polymethylene radicals such as trimethylene, tetramethylene, pentamethylene and hexamethylene.

Among the radicals which R and R. represent are such lower alkyl groups as methyl, ethyl, propyl, butyl, amyl, hexyl, cyclopentyl and cyclohexyl, wherein the propyl, butyl, amyl and hexyl groups may be either of the straight-chain or branched-chain type. The radical NRR' may also be a part of a nitrogen containing heterocyclic group such as a N-piperidino, N-lupetidino, N-pyrrolidino, N'-alkyl-N-piperazino or morpholino group.

The organic bases of the foregoing type form salts with a variety of inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, oxalic, ascorbic and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrodhalic and aromatic acids. Among such esters are methyl chloride and bromide, benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride, dimethyl sulfate, diethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

It is the object of this invention to provide novel chemical substances of the foregoing type. Certain of them are valuable as intermediates in chemical synthesis. For example, new therapeutic agents may be obtained by reduction of the carbonyl group adjoining the Ar group to a carbinol and to a methylenegroup.

The esters of this invention have been found to possess a number of highly useful therapeutic properties. Thus the acid addition salts have a strong regulatory effect on the cardiovascular system. In somerespects this effect on cardiac irregularities is qualitatively similar but quantitatively superior to that of quinidine. Other compounds, especially the quaternary salts, have a ganglion blocking action and act as sympathicolytics and parasympathicolytics. Further, some of these compounds are useful active ingredients in parasiticidal compositions. In the examples quantities of materials are given as parts by weight, uncorrected temperatures as degrees centigrade (C.) and pressures during Vacuum distillation as millimeters (mm.) of

mercury.

EXAMPLE 1 -benzoyl-fl-phenylbutyric acid ester of diethylaminoethanol A mixture of 300 parts of 'y-benzoyl-c-ph en'ylbutyric acid and 160 parts of diethylaminoethyl chloride in 3150 parts of anhydrous propanol is heated at refluxing temperature with stirring for 3-4 hours. The solution is concentrated and the concentrate taken up in water. The aqueous solution is made alkaline by addition of a solution of sodium carbonate and extracted with ether. The ether extract is dried over anhydrous potassium carbonate, filtered and evaporated. The -benzoyl-cphenylbutyric acid ester of diethylaminoethanol is distilled at about 236-8 C. and 1 mm. pressure.

Treatment of an ether solution of the base with a 25% solution of hydrogen chloride inisopropanol yields an oily hydrochloride which solidifies on standing in the'refrigerator. Re-

crystallization from ethyl acetate yields color less crystals melting at about -86 C.

EXAMPLEZ y-benzoyZ-c-phenylbutyric acid ester of (pi-hydram ethyl) diethylmethylammom'um iodide One hundred parts of v-benzoyl-B-phenylbwtyric ester of diethylaminoethanol are heated with a solution of 332 parts of methyl iodide in 3200 parts of butanone at 85 C. in a shielded pressure bottle. .A solid precipitate begins to form within an hour. After 2 hours of heating the mixture is cooled, filtered and washed well with ether. The benzoyl-fi-phenylbutyric acid ester of (Ii-hydroxyethyl) -diethylmethylammonium iodide, after recrystallization from ethanol usin charcoal as a clarifying agent, melts at about 117-118 C. The iodide is converted to the acid tartrate by treatment with mol. of tartaric acid and /2 mol of silver tartrate in cold, absolute methanol. The silver bromide is filtered oil and the filtrate evaporated in vacuo. The cation has the structural formula CaH5C OCHz-CHCHC o O-CHzCHzNC2H5 U 5115 (EH3 EXAMPLE 3 y-benzoz/l-a-phenylbatyric acid ester of diethylaminoethanol A mixture of 268 parts of 'y-bEIlZOYl-a-DhQIlYlbutyric acid and 135 parts of B-chloroethyl-diethylamin in 1600 parts of isopropanol is heated at refluxing temperature with stirring for 2 hours. The resulting solution is concentrated and made alkaline by the addition of dilute sodium carbonate solution. The alkaline solution is extracted with ether and the ether extract is dried over potassium carbonate, filtered and evaporated. The 'y-benzoy1-a-phenylbutyri'c acid ester of diethylaminoethanol is distilled at about 220-222 C. at 2 mm. pressure. An other solution of the base is treated with a solution of hydrogen chloride in anhydrous isopropanol to produce a sticky hydrochloride which solidifies within a few'hours at 0 C. After recrystallization from ethyl acetate, the hydrochloride melts at about 63-65 C.

EXAMPLE 4 v-benzoyl-a-phemylbutyrz'c acid ester 0 (Ii-hydroxyethyl) diethylmetihylammomum bromide In a shielded pressure bottle 120 parts of the 'y-benzoyl-a-phenylbutyric acid ester of diethylaminoethanol are heated with a solution of 120 parts of methyl bromide in 400 parts of butanone for'2 hours. After a short time of storage at 0 C. the -benzoyl-.a-phenylbutyric acid ester of 3- hydroxyethyl)diethylmethylammonium bromide solidifies. It melts at about 10-7-108 C. The bromide is converted into the nitrate by treatment with an equimolar amount of silver nitrate in a large volum of absolute methanol. The silver bromide is filtered oil and the filtrate is evaporated in vacuo. The residue is Washed withether and butanone. The cation has the structural 'y- (o-anz'so yl) -fi-(p-chlorophenyl) butyric acid ester of a-dz'me'thylaminobutanol 'y- (o-anisoyl) 8- (p-chlorophenyD butyric acid is prepared by the method of C. R. Hauser, R. S. Yost, and B. I. Ringler (J. org. chem. 14, 261; 1949) from o-methoxyacetophenone and ethyl pchlorocinnamate. A mixture of 332 parts of this acid and 135 parts of 6-dimethylaminobutyl chlo- EXAMPLE 6 'y-benzo yl-a-(p-tolylhbutyric acid ester of N-(B- hydroxyethyl) morpholine 'y-(ptO1y1) glutaryl anhydride is prepared by the method of E. C. Horning and A. F. Finelli (J. Am. Chem. Soc. 71:3204; 1949) and treated by the method described in the same article with benzene in the presence of aluminum bromide to form 'y-benzoyl-a- (p-tolyDbutyric acid. 190 parts of this acid are then heated with parts of N- (fl-chloroethyl) morpholine in 2000 parts of anhydrous isopropanol at boiling temperature for 4 hours under reflux with strong mechanical agitation. The solvent is removed with vacuum distillation and the concentrate treated with a dilute sodium hydroxide solution. The base is extracted with ether and the ether extract is dried over anhydrous potassium carbonate, filtered and evaporated. The residual oil consists of the 'y-benzoyla- (p-tolyl) butyric acid ester of N- (ii hydroxyethy1)morpholine, which has the structural formula I CH3 I claim:

l. The new group of organic compounds cons1st1ng of the esters of aroylarylbutyric acids of the structural formula and the non-toxic salts thereof, wherein Ar and Ar are members of the group consisting of phenyl radicals and'halogen-, lower alkyland methoxysubstituted phenyl radicals, Yis a loweralkylene radical, and NRR' is a member of the class consisting of lower dialkylamino and morpholino radicals.

2. The .dialkylaminoalkyl estersof -benzoyL ,B-arylbutyric acids of the structural formula wherein Ar" is a lower monocyclic, aromatic, hy-

drocarbon radical, Y is a lower saturated, alkylene radical andRand. 12' are loweralkyl radicals.

2. The dialkylaminoalkyl esters of -benzoyl- B-phenylbutyric acid of the structural formula CaHrCOCH2CH(CaH5)CHzCOO-YN wherein Y is a lower saturated, alkylene radical and R and R are lower alkyl radicals.

4. The dialkylaminoethyl esters of v-benzoylfl-phenylbutyric acid of the structural formula cum-oo-om-omomo-om-ooo-oHPom-N wherein R and R are lower alkyl radicals.

5. The quaternary ammonium salts of dialkylaminoalkyl esters'of -benzoyl-fi-arylbutyric acids of the structural formula F/ CoHs-C O-GHz-CHAN-OHi-O 0YN acids of the structural formula X RI! wherein R, R and R are lower alkyl radicals and X is one equivalent of a non-toxic anion.

8. The dialkylaminoalkyl esters of 'y-b6I1Z0y1-a arylbutyric acids of the structural formula OuHOO--CHaOH-2OHArOOO-Y-N wherein tAr' is a lower monocyclic, aromatic, hydrocarbon radical, Y is a lower saturated, alkylene radical and R and R are lower alkyl radicals.

9. The dialkylaminoalkyl esters of y-benzoyla-phenylbutyric acid of the structural formula CsHg-COCH2CHr-CH(CaHa)COO-YN wherein Y is a lower saturated, alkylene radical and R and R are lower alkyl radicals.

10. The dialkylaminoethyl esters of *y-bBIlZOYI- a-phenylbutyric acid of the structural formula /R oun o O'OHZ-GHTOH(OBHE) G 0 OCHnCHzN wherein R and R are lower alkyl radicals.

11. The quaternary ammonium salts of dialkylaminoalkyl esters of -benzoyl-a-phehylbutyric acids of the structural formula V wherein Y is a lower saturated, alkylene radical,

R, R and R are lower alkyl radicals and X is one equivalent of a non-toxic anion.

12. The quaternary ammonium salts of dialkylaminoethyl esters of -benzoyl-a-phenylbutyric acids of the structural formula i I l CeHsCOCHzOH2OH(OaH5)COOOHzOHzN wherein R, R and R are lower alkylradicals and X is one equivalent of a non-toxic anion. 13. The quaternary ammonium salts of dialkylaminoalkyl esters of y-benzoyl-a-arylbutyric esters of the structural formula 06115-0 o-oH2oH,-o H o@H@)-oooY-N wherein Y is'a lower saturated, bivalent, aliphatic hydrocarbon radical, R, R and R are lower alkyl radicals and X is one equivalent of a nontoxic anion.

7 logen JOHN W. CUSIC.

References Cited in the file of this patent Blicke et al., J. Am. Chem. Soc., vol. 64, p. 430.

Borsche, Chem. Abs, vol. 4, p. 590. 

1. THE NEW GROUP OF ORGANIC COMPOUNDS CONSISTING OF THE ESTERS OF AROYLARYLBUTYRIC ACID OF THE STRUCTURAL FORMULA 